Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains ...unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis.
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and ...neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.
Many neutron star properties, such as the proton fraction, reflect the symmetry energy contributions to the equation of state that dominate when neutron and proton densities differ strongly. To ...constrain these contributions at suprasaturation densities, we measure the spectra of charged pions produced by colliding rare isotope tin (Sn) beams with isotopically enriched Sn targets. Using ratios of the charged pion spectra measured at high transverse momenta, we deduce the slope of the symmetry energy to be 42<L<117 MeV. This value is slightly lower but consistent with the L values deduced from a recent measurement of the neutron skin thickness of ^{208}Pb.
The pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. This study ...aims to characterise the mucosal virome and their functions in health and UC.
Deep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2.
In UC, there was an expansion of mucosa viruses, particularly
bacteriophages, and a decrease in mucosa
diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls.
and
were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC.
We demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of
bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.
HIAF (High Intensity heavy ion Accelerator Facility), a new facility planned in China for heavy ion related researches, consists of two ion sources, a high intensity Heavy Ion Superconducting Linac ...(HISCL), a 45 Tm Accumulation and Booster Ring (ABR-45) and a multifunction storage ring system. The key features of HIAF are unprecedented high pulse beam intensity and versatile operation mode. The HIAF project aims to expand nuclear and related researches into presently unreachable region and give scientists possibilities to conduct cutting-edge researches in these fields. The general description of the facility is given in this article with a focus on the accelerator design.
Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot ...penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.
It is a huge challenge in both classical and quantum physics to solve analytically the equation of motion in a strongly anharmonic confinement. For an isolated nanoring, we propose a continuous and ...bounded potential model, which patches up the disadvantages of the usual square-well and parabolic potentials. A fully nonlinear and nonperturbative approach is developed to solve analytically the equation of motion, from which various frequency shifts and dynamic displacements are exactly derived by an order-by-order self-consistent method. A series of new energy levels and new energy states are found, indicating an alternative magnetic response mechanism. In nominally identical rings, especially, we observe a diamagnetic-paramagnetic transition in the period-halving Φ
/2-current with Φ
the flux quantum and a large increase in the Φ
-current at least one order of magnitude, which explain well the experimental observations. This work opens a new way to solve the strong or weak nonlinear problems.
Host immune peptides, including cathelicidins, have been reported to possess anticancer properties. We previously reported that LL-37, the only cathelicidin in humans, suppresses the development of ...colon cancer. In this study, the potential anticancer effect of FK-16, a fragment of LL-37 corresponding to residues 17 to 32, on cultured colon cancer cells was evaluated. FK-16 induced a unique pattern of cell death, marked by concurrent activation of caspase-independent apoptosis and autophagy. The former was mediated by the nuclear translocation of AIF and EndoG whereas the latter was characterized by enhanced expression of LC3-I/II, Atg5 and Atg7 and increased formation of LC3-positive autophagosomes. Knockdown of Atg5 or Atg7 attenuated the cytotoxicity of FK-16, indicating FK-16-induced autophagy was pro-death in nature. Mechanistically, FK-16 activated nuclear p53 to upregulate Bax and downregulate Bcl-2. Knockdown of p53, genetic ablation of Bax, or overexpression of Bcl-2 reversed FK-16-induced apoptosis and autophagy. Importantly, abolition of AIF/EndoG-dependent apoptosis enhanced FK-16-induced autophagy while abolition of autophagy augmented FK-16-induced AIF-/EndoG-dependent apoptosis. Collectively, FK-16 induces caspase-independent apoptosis and autophagy through the common p53-Bcl-2/Bax cascade in colon cancer cells. Our study also uncovered previously unknown reciprocal regulation between these two cell death pathways.
Abstract We report the phase-resolved spectral results of the first Galactic pulsating ultraluminous X-ray source (PULX) Swift J0243.6+6124, modeling its 2017–2018 outburst peak using data collected ...by the Hard X-ray Modulation Telescope (Insight-HXMT). The broad energy coverage of Insight-HXMT allows us to obtain a more accurate spectral continuum to reduce the coupling of broad iron line profiles with other components. We use three different continuum spectrum models but obtain similar iron line results. For the first time, we detect the pulse characteristics of the broad iron line in a PULX. The variation in the width and intensity of this iron line with σ ∼ 1.2–1.5 keV has a phase offset of about 0.25 from the pulse phase. We suggest that the uneven irradiation of the thick inner disk by the accretion column produces the modulated variation of the broad iron line. In addition, the nonpulsed narrow line is suggested to come from the outer disk region.
A
bstract
Based on 4.5 fb
−
1
data taken at seven center-of-mass energies ranging from 4.600 to 4.699 GeV with the BESIII detector at the BEPCII collider, we measure the branching fractions of
Λ
c
+
...→
Σ
+
+
hadrons
relative to
Λ
c
+
→
Σ
+
π
+
π
−
. Combining with the world average branching fraction of
Λ
c
+
→
Σ
+
π
+
π
−
, their branching fractions are measured to be (0
.
377
±
0
.
042
±
0
.
020
±
0
.
021)% for
Λ
c
+
→
Σ
+
K
+
K
−
, (0
.
200
±
0
.
023
±
0
.
011
±
0
.
011)% for
Λ
c
+
→
Σ
+
K
+
π
−
, (0
.
414
±
0
.
080
±
0
.
030
±
0
.
023)% for
Λ
c
+
→
Σ
+
ϕ
and (0
.
197
±
0
.
036
±
0
.
009
±
0
.
011)% for
Λ
c
+
→ Σ
+
K
+
K
−
(non-
ϕ
). In all the above results, the first uncertainties are statistical, the second are systematic and the third are from external input of the branching fraction of
Λ
c
+
→
Σ
+
π
+
π
−
. Since no signal for
Λ
c
+
→
Σ
+
K
+
π
−
π
0
is observed, the upper limit of its branching fraction is determined to be 0.13% at the 90% confidence level.
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